1. Field of the Invention
This invention relates generally to the noninvasive measurement of biological parameters through near-infrared spectroscopy. In particular, an apparatus and a method are disclosed for noninvasively, and continuously or semi-continuously, monitoring a biological parameter, such as glucose in tissue.
2. Discussion of the Prior Art
Diabetes
Diabetes is a chronic disease that results in improper production and use of insulin, a hormone that facilitates glucose uptake into cells. Diabetes can be broadly categorized into four forms: diabetes, impaired glucose tolerance, normal physiology, and hyperinsulinemia (hypoglycemia). While a precise cause of diabetes is unknown, genetic factors, environmental factors, and obesity appear to play roles.
Diabetics have increased risk in three broad categories: cardiovascular heart disease, retinopathy, and neuropathy. Diabetics may have one or more of the following complications: heart disease and stroke, high blood pressure, kidney disease, neuropathy (nerve disease and amputations), retinopathy, diabetic ketoacidosis, skin conditions, gum disease, impotence, and fetal complications. Diabetes is a leading cause of death and disability worldwide.
Diabetes Prevalence and Trends
Diabetes is a common and growing disease. The World Health Organization (WHO) estimates that diabetes currently afflicts one hundred fifty-four million people worldwide. Fifty-four million diabetics live in developed countries. The WHO estimates that the number of people with diabetes will grow to three hundred million by the year 2025. In the United States, 15.7 million people or 5.9% of the population are estimated to have diabetes. Within the United States, the prevalence of adults diagnosed with diabetes increased by six percent in 1999 and rose by thirty-three percent between 1990 and 1998. This corresponds to approximately eight hundred thousand new cases every year in America. The estimated total cost to the United States economy alone exceeds $90 billion per year (Diabetes Statistics. Bethesda, MD: National Institute of Health, Publication No. 98-3926, November 1997).
Long-term clinical studies show that the onset of diabetes related complications can be significantly reduced through proper control of blood glucose concentrations (The Diabetes Control and Complications Trial Research Group. The effect of intensive treatment of diabetes on the development and progression of long-term complications in insulin-dependent diabetes mellitus. N Eng J of Med 1993;329:977-86; U.K. Prospective Diabetes Study (UKPDS) Group, “Intensive blood-glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes,” Lancet, vol. 352, pp. 837-853, 1998; Ohkubo, Y., H. Kishikawa, E. Araki, T. Miyata, S. Isami, S. Motoyoshi, Y. Kojima, N. Furuyoshi, and M. Shichizi, “Intensive insulin therapy prevents the progression of diabetic microvascular complications in Japanese patients with non-insulin-dependent diabetes mellitus: a randomized prospective 6-year study,” Diabetes Res Clin Pract, vol. 28, pp. 103-117, 1995). A vital element of diabetes management is the self-monitoring of blood glucose levels by diabetics in the home environment. However, current monitoring techniques discourage regular use due to the inconvenient and painful nature of drawing blood through the skin prior to analysis (The Diabetes Control and Complication Trial Research Group, “The effect of intensive treatment of diabetes on the development and progression of long-term complications of insulin-dependent diabetes mellitus”, N. Engl. J. Med., 329, 1993, 997-1036). Unfortunately, recent reports indicate that even periodic measurement of glucose by individuals with diabetes, (e.g. seven times per day) is insufficient to detect important glucose fluctuations and properly manage the disease. In addition, nocturnal monitoring of glucose levels is of significant value but is difficult to perform due to the state of existing technology. Therefore, a device that provides noninvasive, automatic, and nearly continuous measurements of glucose levels would be of substantial value to people with diabetes. Implantable glucose analyzers eventually coupled to an insulin delivery system providing an artificial pancreas are also being pursued.
Description of Related Technology
Common technologies are used to analyze the blood glucose concentration of samples collected by venous draw and with capillary stick approaches. Glucose analysis includes techniques such as colorimetric and enzymatic glucose analysis. Many of the invasive, traditional invasive, alternative invasive, and minimally invasive glucose analyzers use these technologies. The most common enzymatic based glucose analyzers use glucose oxidase, which catalyzes the reaction of glucose with oxygen to form gluconolactone and hydrogen peroxide, equation 1. Glucose determination may be achieved by techniques based upon depletion of oxygen in the sample, through the changes in sample pH, or via the formation of hydrogen peroxide. A number of colorimetric and electro-enzymatic techniques further use the reaction products as a starting reagent. For example, hydrogen peroxide reacts in the presence of platinum to form the hydrogen ion, oxygen, and current any of which may be used to determine the glucose concentration, equation 2.glucose+O2→gluconolactone+H2O2   eq. 1H2O2→2H++O2+2e−  eq. 2
Due to the wide and somewhat loose terminology in the field, the terms traditional invasive, alternative invasive, noninvasive, and implantable are here outlined:
Traditional Invasive Glucose Determination
There are three major categories of traditional (classic) invasive glucose determinations. The first two methodologies use blood drawn with a needle from an artery or vein, respectively. The third group consists of capillary blood obtained via lancet from the fingertip or toes. Over the past two decades, this last method has become the most common method for self-monitoring of blood glucose at home, at work, or in public settings.
Alternative Invasive Glucose Determination
There are several alternative invasive methods of determining glucose concentrations.
A first group of alternative invasive glucose analyzers have a number of similarities to traditional invasive glucose analyzers. One similarity is that blood samples are acquired with a lancet. Obviously, this form of alternative invasive glucose determination may not be used to collect venous or arterial blood for analysis, but may be used to collect capillary blood samples. A second similarity is that the blood sample is analyzed using chemical analyses that are similar to the calorimetric and enzymatic analyses describe above. The primary difference is that in an alternative invasive glucose determination the blood sample is not collected from the fingertip or toes. For example, according to package labeling the TheraSense® FreeStyle Meter™ may be used to collect and analyze blood from the forearm. This is an alternative invasive glucose determination due to the location of the lancet draw.
In this first group of alternative invasive methods based upon blood draws with a lancet, a primary difference between the alternative invasive and traditional invasive glucose determination is the location of blood acquisition from the body. Additional differences include factors such as the gauge of the lancet, the depth of penetration of the lancet, timing issues, the volume of blood acquired, and environmental factors such as the partial pressure of oxygen, altitude, and temperature. This form of alternative invasive glucose determination includes samples collected from the palmar region, base of thumb, forearm, upper arm, head, earlobe, torso, abdominal region, thigh, calf, and plantar region.
A second group of alternative invasive glucose analyzers are distinguished by their mode of sample acquisition. This group of glucose analyzers has a common characteristic of acquiring a biological sample from the body or modifying the surface of the skin to gather a sample without use of a lancet for subsequent analysis. For example, a laser poration based glucose analyzer would use a burst or stream of photons to create a small hole in the surface of the skin. A sample of basically interstitial fluid would collect in the resulting hole. Subsequent analysis of the sample for glucose would constitute an alternative invasive glucose analysis whether or not the sample was actually removed from the created hole. A second common characteristic is that a device and algorithm are used to determine glucose from the sample.
A number of methodologies exist for the collection of the sample for alternative invasive measurements including laser poration, applied current, and suction. The most common are summarized here:    A. Laser poration: In these systems, photons of one or more wavelengths are applied to skin creating a small hole in the skin barrier. This allows small volumes of interstitial fluid to become available to a number of sampling techniques.    B. Applied current: In these systems, a small electrical current is applied to the skin allowing interstitial fluid to permeate through the skin.    C. Suction: In these systems, a partial vacuum is applied to a local area on the surface of the skin. Interstitial fluid permeates the skin and is collected.
For example, a device that acquires a sample via iontophoresis, such as Cygnus'® GlucoWatch™, is an alternative invasive technique.
In all of these techniques, the analyzed sample is interstitial fluid. However, some of the techniques can be applied to the skin in a fashion that draws blood. Herein, the term alternative invasive includes techniques that analyze biosamples such as interstitial fluid, whole blood, mixtures of interstitial fluid and whole blood, and selectively sampled interstitial fluid. An example of selectively sampled interstitial fluid is collected fluid in which large or less mobile constituents are not fully represented in the resulting sample. For this group of alternative invasive glucose analyzers sampling sites include: the hand, fingertips, palmar region, base of thumb, forearm, upper arm, head, earlobe, eye, chest, torso, abdominal region, thigh, calf, foot, plantar region, and toes. In this document, any technique that draws biosamples from the skin without the use of a lancet on the fingertip or toes is referred to as an alternative invasive technique.
In addition, it is recognized that the alternative invasive systems each have different sampling approaches that lead to different subsets of the interstitial fluid being collected. For example, large proteins might lag behind in the skin while smaller, more diffusive, elements may be preferentially sampled. This leads to samples being collected with varying analyte and interferent concentrations. Another example is that a mixture of whole blood and interstitial fluid may be collected. Another example is that a laser poration method can result in blood droplets. These techniques may be used in combination. For example the Soft-Tact, SoftSense in Europe, applies a suction to the skin followed by a lancet stick. Despite the differences in sampling, these techniques are referred to as alternative invasive techniques sampling interstitial fluid.
Sometimes, the literature refers to the alternative invasive technique as an alternative site glucose determination or as a minimally invasive technique. The minimally invasive nomenclature derives from the method by which the sample is collected. In this document, the alternative site glucose determinations that draw blood or interstitial fluid, even ¼ microliter, are considered to be alternative invasive glucose determination techniques as defined above. Examples of alternative invasive techniques include the TheraSense® FreeStyle™ when not sampling fingertips or toes, the Cygnus® GlucoWatch™, the One Touch® Ultra™, and equivalent technologies.
Biosamples collected with alternative invasive techniques are analyzed via a large range of technologies. The most common of these technologies are summarized below:    A. Conventional: With some modification, the interstitial fluid samples may be analyzed by most of the technologies used to determine glucose concentrations in serum, plasma, or whole blood. These include electrochemical, electroenzymatic, and calorimetric approaches. For example, the enzymatic and colorimetric approaches described above may also be used to determine the glucose concentration in interstitial fluid samples.    B. Spectrophotometric: A number of approaches, for determining the glucose concentration in biosamples, have been developed that are based upon spectrophotometric technologies. These techniques include: Raman and fluorescence, as well as techniques using light from the ultraviolet through the infrared [ultraviolet (200 to 400 nm), visible (400 to 700 nm), near-IR (700 to 2500 nm or 14,286 to 4000 cm−1), and infrared (2500 to 14,285 nm or 4000 to 700 cm−1)].
In this document, an invasive glucose analyzer is the genus of both the traditional invasive glucose analyzer species and the alternative invasive glucose analyzer species.
Noninvasive Glucose Determination
There exist a number of noninvasive approaches for glucose determination. These approaches vary widely, but have at least two common steps. First, an apparatus is used to acquire a reading from the body without obtaining a biological sample. Second, an algorithm is used to convert this reading into a glucose determination.
One species of noninvasive glucose analyzers are those based upon the collection and analysis of spectra. Typically, a noninvasive apparatus uses some form of spectroscopy to acquire the signal or spectrum from the body. Used spectroscopic techniques include but are not limited to Raman, fluorescence, as well as techniques using light from ultraviolet through the infrared [ultraviolet (200 to 400 nm), visible (400 to 700 nm), near-IR (700 to 2500 nm or 14,286 to 4000 cm−1), and infrared (2500 to 14,285 nm or 4000 to 700 cm−1)]. A particular range for noninvasive glucose determination in diffuse reflectance mode is about 1100 to 2500 nm or ranges therein (Hazen, Kevin H. “Glucose Determination in Biological Matrices Using Near-infrared Spectroscopy”, doctoral dissertation, University of Iowa, 1995). It is important to note, that these techniques are distinct from the traditionally invasive and alternative invasive techniques listed above in that the sample analyzed is a portion of the human body in-situ, not a biological sample acquired from the human body.
Typically, three modes are used to collect noninvasive scans: transmittance, transflectance, and/or diffuse reflectance. For example the light, spectrum, or signal collected may be light transmitting through a region of the body, diffusely transmitting, diffusely reflected, or transflected. Transflected here refers to collection of the signal not at the incident point or area (diffuse reflectance), and not at the opposite side of the sample (transmittance), but rather at some point or region of the body between the transmitted and diffuse reflectance collection area. For example, transflected light enters the fingertip or forearm in one region and exits in another region. When using the near-IR, the transflected radiation typically radially disperses 0.2 to 5 mm or more away from the incident photons depending on the wavelength used. For example, light that is strongly absorbed by the body such as light near the water absorbance maxima at 1450 or 1950 nm must be collected after a small radial divergence in order to be detected and light that is less absorbed such as light near water absorbance minima at 1300, 1600, or 2250 nm may be collected at greater radial or transflected distances from the incident photons.
Noninvasive techniques are not limited to the fingertip. Other regions or volumes of the body subjected to noninvasive measurements are: a hand, finger, palmar region, base of thumb, forearm, volar aspect of the forearm, dorsal aspect of the forearm, upper arm, head, earlobe, eye, tongue, chest, torso, abdominal region, thigh, calf, foot, plantar region, and toe. It is important to note that noninvasive techniques do not have to be based upon spectroscopy. For example, a bioimpedence meter would be a noninvasive device. In this document, any device that reads glucose from the body without penetrating the skin and collecting a biological sample is referred to as a noninvasive glucose analyzer. For the purposes of this document, X-rays and MRI's are not considered to be defined in the realm of noninvasive technologies.
Implantable Sensor for Glucose Determination
There exist a number of approaches for implanting a glucose sensor into the body for glucose determination. These implantables may be used to collect a sample for further analysis or may acquire a reading of the sample directly or based upon direct reactions occurring with glucose. Two categories of implantable glucose analyzers exist: short-term and long-term.
In this document, a device or a collection apparatus is referred to as a short-term implantable (as opposed to a long-term implantable) if part of the device penetrates the skin for a period of greater than three hours and less than one month. For example, a wick placed subcutaneously to collect a sample overnight that is removed and analyzed for glucose content representative of the interstitial fluid glucose concentration is referred to as a short term implantable. Similarly, a biosensor or electrode placed under the skin for a period of greater than three hours that reads directly or based upon direct reactions occurring with glucose concentration or level is referred to as a short-term implantable device. Conversely, devices such as a lancet, applied current, laser poration, or suction are referred to as either a traditional invasive or alternative invasive technique as they do not fulfill both the three hour and penetration of skin parameters. An example of a short-term implantable glucose analyzer is MiniMed's® continuous glucose monitoring system. In this document, long-term implantables are distinguished from short-term implantables by having the criteria that they must both penetrate the skin and be used for a period of one month or longer. Long term implantables may be in the body for greater than one month, one year, or many years.
Implantable glucose analyzers vary widely, but have at least several steps in common. First, at least part of the device penetrates the skin. More commonly, the entire device is imbedded into the body. Second, the apparatus is used to acquire either a sample of the body or a signal relating directly or based upon direct reactions occurring with the glucose concentration within the body. If the implantable device collects a sample, readings or measurements on the sample may be collected after removal from the body. Alternatively, readings may be transmitted out of the body by the device or used for such purposes as insulin delivery while in the body. Third, an algorithm is used to convert the signal into a reading directly or based upon direct reactions occurring with the glucose concentration. An implantable analyzer may read from one or more of a variety of body fluids or tissues including but not limited to: arterial blood, venous blood, capillary blood, interstitial fluid, and selectively sampled interstitial fluid. An implantable analyzer may also collect glucose information from skin tissue, cerebral spinal fluid, organ tissue, or through an artery or vein. For example, an implantable glucose analyzer may be placed transcutaneously, in the peritoneal cavity, in an artery, in muscle, or in an organ such as the liver or brain. The implantable glucose sensor may be one component of an artificial pancreas.
Description of Related Technology
One class of alternative invasive continuous glucose monitoring systems are those based upon iontophoresis. Using the iontophoresis process, uncharged molecules such as glucose may be moved across the skin barrier with the application of a small electric current. Several patents and publications in this area are available (Tamada, J. A., S. Garg, L. Jovanovic, K. R. Pitzer, S. Fermi, R. O. Potts, “Noninvasive Glucose Monitoring Comprehensive Clinical Results,” JAMA, Vol. 282, No. 19, pp. 1839-1844, Nov. 17, 1999; Berner, Bret; Dunn, Timothy c.; Farinas, Kathleen C.; Garrison, Michael D.; Kurnik, Ronald T.; Lesho, Matthew J.; Potts, Russell O.; Tamada, Janet A.; Tierney, Michael J. “Signal Processing for Measurement of Physiological Analysis”, U.S. Pat. No. 6,233,471, May 15, 2001; Dunn, Timothy C.; Jayalakshmi, Yalia; Kurnik, Ronald T.; Lesho, Matthew J.; Oliver, Jonathan James; Potts, Russell O.; Tamada, Janet A.; Waterhouse, Steven Richard; Wei, Charles W. “Microprocessors for use in a Device Predicting Physiological Values”, U.S. Pat. No. 6,326,160, Dec. 4, 2001; Kurnik, Ronald T. “Method and Device for Predicting Physiological Values”, U.S. Pat. No. 6,272,364, Aug. 7, 2001; Kurnik, Ronald T.; Oliver, Jonathan James; Potts, Russell O.; Waterhouse, Steven Richard; Dunn, Timothy C.; Jayalakshmi, Yalia; Lesho, Matthew J.; Tamada, Janet A.; Wei, Charles W. “Method and Device for Predicting Physiological Values”, U.S. Pat. No. 6,180,416, Jan. 30, 2001; Tamada, Janet A.; Garg, Satish; Jovanovic, Lois; Pitzer, Kenneth R.; Fermi, Steve; Potts, Russell O. “Noninvasive Glucose Monitoring”, JAMA, 282, 1999, 1839-1844; Sage, Burton H. “FDA Panel Approves Cygnus's Noninvasive GlucoWatch™”, Diabetes Technology & Therapeutics, 2, 2000, 115-116; and “GlucoWatch Automatic Glucose Biographer and AutoSensors”, Cygnus Inc., Document #1992-00, Rev. March 2001) The Cygnus Glucose Watch® uses this technology. The GlucoWatch® provides only one reading every twenty minutes, each delayed by at least ten minutes due to the measurement process. The measurement is made through an alternative invasive electrochemical-enzymatic sensor on a sample of interstitial fluid which is drawn through the skin using iontophoresis. Consequently, the limitations of the device include the potential for significant skin irritation, collection of a biohazard, and a limit of three readings per hour.
One class of semi-implantable glucose analyzers are those based upon open-flow microperfusion (Trajanowski, Zlatko; Brunner, Gernot A.; Schaupp, Lucas; Ellmerer, Martin; Wach, Paul; Pieber, Thomas R,; Kotanko, Peter; Skrabai, Falko “Open-Flow Microperfusion of Subcutaneous Adipose Tissue for ON-Line Continuous Ex Vivo Measurement of Glucose Concentration”, Diabetes Care, 20, 1997, 1114-1120). Typically these systems are based upon biosensors and amperometric sensors (Trajanowski, Zlatko; Wach, Paul; Gfrerer, Robert “Portable Device for Continuous Fractionated Blood Sampling and Continuous ex vivo Blood Glucose Monitoring”, Biosensors and Bioelectronics, 11, 1996, 479-487). A common issue with semi-implantable and implantable devices is coating by proteins. The MiniMed® continuous glucose monitoring system, a short-term implantable, is the first commercially available semi-continuous glucose monitor in this class. The MiniMed® system is capable of providing a glucose profile for up to seventy-two hours. The system records a glucose value every five minutes. The technology behind the MiniMed® system relies on a probe being invasively implanted into a subcutaneous region followed by a glucose oxidase based reaction producing hydrogen peroxide, which is oxidized at a platinum electrode to produce an analytical current. Notably, the MiniMed® system automatically shifts glucose determinations by ten minutes in order to accommodate for a potential dynamic lag between the blood and interstitial glucose (Gross, Todd M.; Bode, Bruce W.; Einhorn, Daniel; Kayne, David M.; Reed, John H.; White, Neil H.; Mastrototaro, John J. “Performance Evaluation of the MiniMed Continuous Glucose Monitoring System During Patient Home Use”, Diabetes Technology & Therapeutics, 2, 2000, 49-56.; Rebrin, Kerstin; Steil, Gary M.; Antwerp, William P. Van; Mastrototaro, John J. “Subcutaneous Glucose Predicts Plasma Glucose Independent of Insulin: Implications for Continuous Monitoring”, Am., J. Physiol., 277, 1999, E561-E571, 0193-1849/99, The American Physiological Society, 1999).
Other approaches, such as the continuous monitoring system reported by Gross, et. al. (Gross, T. M., B. W. Bode, D. Einhorn, D. M. Kayne, J. H. Reed, N. H. White and J. J. Mastrototaro, “Performance Evaluation of the MiniMed® Continuous Glucose Monitoring System During Patient Home Use,” Diabetes Technology & Therapeutics, Vol. 2, Num. 1, 2000), involve the implantation of a sensor in tissue with a transcutaneous external connector. Inherent in these approaches are health risks due to the sensor implantation, infections, patient inconvenience, and measurement delay.
Another approach towards continuous glucose monitoring is through the use of fluorescence. For example Sensors for Medicine and Science Incorporated (S4MS) is developing a glucose selective indicator molecule combined into an implantable device that is coupled via telemetry to an external device. The device works via an indicator molecule that reversibly binds to glucose. With an LED for excitation, the indicator molecule fluoresces in the presence of glucose. This device is an example of a short-term implantable with development towards a long-term implantable (Colvin, Arthur E. “Optical-Based Sensing Devices Especially for In-Situ Sensing in Humans”, U.S. Pat. No. 6,304,766, Oct. 16, 2001; Colvin, Arthur E.; Dale, Gregory A.; Zerwekh, Samuel, Lesho, Jeffery C.; Lynn, Robert W. “Optical-Based Sensing Devices”, U.S. Pat. No. 6,330,464, Dec. 11, 2001; Colvin, Arthur E.; Daniloff, George Y.; Kalivretenos, Aristole G.; Parker, David; Ullman, Edwin E.; Nikolaitchik, Alexandre V. “Detection of Analytes by fluorescent Lanthanide Metal Chelate Complexes Containing Substituted Ligands”, U.S. Pat. No. 6,334,360, Feb. 5, 2002; and Lesho, Jeffery “Implanted Sensor Processing System and Method for Processing Implanted Sensor Output”, U.S. Pat. No. 6,400,974, Jun. 4, 2002).
Notably, none of these technologies are noninvasive. Further, none of these technologies offer continuous glucose determination.
Another technology, near-infrared spectroscopy, provides the opportunity to measure glucose noninvasively with a relativity short sampling interval. This approach involves the illumination of a spot on the body with near-infrared electromagnetic radiation (light in the wavelength range 700 to 2500 nm). The incident light is partially absorbed and scattered, according to its interaction with the constituents of the tissue. The actual tissue volume that is sampled is the portion of irradiated tissue from which light is diffusely reflected, transflected, or transmitted by the sample and optically coupled to the spectrometer detection system. The signal due to glucose is extracted from the spectral measurement through various methods of signal processing and one or more mathematical models. The models are developed through the process of calibration on the basis of an exemplary set of spectral measurements and associated reference blood glucose values (the calibration set) based on an analysis of capillary (fingertip), alternative invasive samples, or venous blood. To date, only discrete glucose determinations have been reported using near-IR technologies.
There exists a body of work on noninvasive glucose determination using near-IR technology, the most pertinent of which are referred here (Robinson, Mark Ries; Messerschmidt, Robert G “Method for Non-invasive Blood Analyte Measurement with Improved Optical Interface”, U.S. Pat. No. 6,152,876, Nov. 28, 2000; Messerschmidt, Robert G.; Robinson, Mark Ries “Diffuse Reflectance Monitoring Apparatus”, U.S. Pat. No. 5,935,062, Aug. 10, 1999; Messerschmidt, Robert G. “Method for Non-invasive Analyte Measurement with Improved Optical Interface”, U.S. Pat. No. 5,823,951, Oct. 20, 1998; Messerschmidt, Robert G. “Method for Non-invasive Blood Analyte Measurement with Improved Optical Interface”, U.S. Pat. No. 5,655,530; Rohrscheib, Mark; Gardner, Craig; Robinson, Mark R. “Method and Apparatus for Non-invasive Blood Analyte Measurement with Fluid Compartment Equilibration”, U.S. Pat. No. 6,240,306, May 29, 2001; Messerschmidt, Robert G.; Robinson, Mark Ries “Diffuse Reflectance Monitoring Apparatus”, U.S. Pat. No. 6,230,034, May 8, 2001; Barnes, Russell H.; Brasch, Jimmie W. “Non-invasive Determination of Glucose Concentration in Body of Patients”, U.S. Pat. No. 5,070,874, Dec. 10, 1991; and Hall, Jeffrey; Cadell, T. E. “Method and Device for Measuring Concentration Levels of Blood Constituents Non-invasively”, U.S. Pat. No. 5,361,758, Nov. 8, 1994). Several Sensys Medical patents also address noninvasive glucose analyzers: Schlager, Kenneth J. “Non-invasive Near Infrared Measurement of Blood Analyte Concentrations”, U.S. Pat. No. 4,882,492, Nov. 21, 1989.; Malin, Stephen; Khalil, Gamal “Method and Apparatus for Multi-Spectral Analysis in Noninvasive Infrared Spectroscopy”, U.S. Pat. No. 6,040,578, Mar. 21, 2000; Garside, Jeffrey J.; Monfre, Stephen; Elliott, Barry C.; Ruchti, Timothy L.; Kees, Glenn Aaron “Fiber Optic Illumination and Detection Patterns, Shapes, and Locations for Use in Spectroscopic Analysis”, U.S. Pat. No. 6,411,373, Jun. 25, 2002; Blank, Thomas B.; Acosta, George; Mattu, Mutua; Monfre, Stephen L. “Fiber Optic Probe and Placement Guide”, U.S. Pat. No. 6,415,167, Jul. 2, 2002; and Wenzel, Brian J.; Monfre, Stephen L.; Ruchti, Timothy L.; Meissner, Ken; Grochocki, Frank “A Method for Quantification of Stratum Corneum Hydration Using Diffuse Reflectance Spectroscopy”, U.S. Pat. No. 6,442,408, Aug. 27, 2002.
Mode of Analysis
A measurement of glucose is termed “direct” when the net analyte due to the absorption of light by glucose in the tissue is extracted from the spectral measurement through various methods of signal processing and/or one or more mathematical models. In this document, an analysis is referred to as direct if the analyte of interest is involved in a chemical reaction. For example, in equation 1 glucose reacts with oxygen in the presence of glucose oxidase to form hydrogen peroxide and gluconolactone. The reaction products may be involved in subsequent reactions such as that in equation 2. The measurement of any reaction component or product is a direct reading of glucose, herein. In this document, a direct reading of glucose would also entail any reading in which the electromagnetic signal generated is due to interaction with glucose or a compound of glucose. For example, the fluorescence approach listed above by Sensors for Medicine and Science is termed a direct reading of glucose, herein.
A measurement of glucose is termed “indirect” when movement of glucose within the body affects physiological parameters. In brief, an indirect glucose determination may be based upon a change in glucose concentration causing an ancillary physiological, physical, or chemical response that is relatively large. A key finding related to the noninvasive measurement of glucose is that a major physiological response accompanies changes in glucose and can be detected noninvasively through the resulting changes in tissue properties.
An indirect measurement of blood glucose through assessment of correlated tissue properties and/or physiological responses requires a different strategy when compared with the direct measurement of glucose spectral signals. Direct measurement of glucose requires the removal of spectral variation due to other constituents and properties in order to enhance the net analyte signal of glucose. Because the signal directly attributable to glucose in tissue is small, an indirect calibration to correlated constituents or properties, e.g. the physiological response to glucose, is attractive due to a gain in relative signal size. For example, changes in the concentration of glucose alters the distribution of water in the various tissue compartments. Because water has a large NIR signal that is relatively easy to measure compared to glucose, a calibration based at least in part on the compartmental activity of water has a magnified signal related to glucose. An indirect measurement may be referred to as a measurement of an ancillary effect of the target analyte. An indirect measurement means that an ancillary effect due to changes in glucose concentration is being measured.
A major component of the body is water. A re-distribution of water between the vascular and extravascular compartments and the intra- and extra-cellar compartments is observed as a response to differences in glucose concentrations in the compartments during periods of changing blood glucose. Water, among other analytes, is shifted between the tissue compartments to equilibrate the osmotic imbalance related to changes in glucose concentration as predicted by Fick's law of diffusion and the fact that water diffuses much faster in the body than does glucose. Therefore, a strategy for the indirect measurement of glucose that exploits the near-infrared signal related to fluid re-distribution is to design measurement protocols that force maximum correlation between blood glucose and the re-distribution of fluids. This is the opposite strategy of the one required for the direct measurement of blood glucose in which the near-infrared signals directly related to glucose and fluids must be discriminated and attempts at equalizing glucose in the body compartment are made. A reliable indirect measurement of glucose based at least in part in the re-distribution of fluids and analytes (other than glucose) and related changes in the optical properties of tissue requires that the indirect signals are largely due to the changing blood glucose concentration. Other variables and sources that modify or change the indirect signals of interest should be prevented or minimized in order to ensure a reliable indirect measurement of glucose.
One interference to a determination of blood/tissue glucose concentration measured indirectly is a rapid change in blood perfusion, which also leads to fluid movement between the compartments. This type of physiological change interferes constructively or destructively with the analyte signal of the indirect measurement. In order to preserve a blood glucose/fluid shift calibration it is beneficial to control other factors influencing fluid shifts including local blood perfusion.
Near-IR Instrumentation
A number of technologies have been reported for measuring glucose noninvasively that involve the measurement of a tissue related variable. One species of noninvasive glucose analyzers use some form of spectroscopy to acquire the signal or spectrum from the body. Examples include but are not limited to far-infrared absorbance spectroscopy, tissue impedance, Raman, and fluorescence, as well as techniques using light from the ultraviolet through the infrared [ultraviolet (200 to 400 nm), visible (400 to 700 nm), near-IR (700 to 2500 nm or 14,286 to 4000 cm−1), and infrared (2500 to 14,285 nm or 4000 to 700 cm−1)]. A particular range for noninvasive glucose determination in diffuse reflectance mode is about 1100 to 2500 nm or ranges therein (Hazen, Kevin H. “Glucose Determination in Biological Matrices Using Near-Infrared Spectroscopy”, doctoral dissertation, University of Iowa, 1995). It is important to note, that these techniques are distinct from invasive techniques in that the sample analyzed is a portion of the human body in-situ, not a biological sample acquired from the human body. The actual tissue volume that is sampled is the portion of irradiated tissue from which light is diffusely reflected, transflected, or diffusely transmitted to the spectrometer detection system. These techniques share the common characteristic that a calibration is required to derive a glucose concentration from subsequent collected data.
A number of spectrometer configurations exist for collecting noninvasive spectra of regions of the body. Typically a spectrometer has one or more beam paths from a source to a detector. A light source may include a blackbody source, a tungsten-halogen source, one or more LED's, or one or more laser diodes. For multi-wavelength spectrometers a wavelength selection device may be used or a series of optical filters may be used for wavelength selection. Wavelength selection devices include dispersive elements such as one or more plane, concave, ruled, or holographic grating. Additional wavelength selective devices include an interferometer, successive illumination of the elements of an LED array, prisms, and wavelength selective filters. However, variation of the source such as varying which LED or diode is firing may be used. Detectors may be in the form of one or more single element detectors or one or more arrays or bundles of detectors. Detectors may include InGaAs, extended InGaAs, PbS, PbSe, Si, MCT, or the like. Detectors may further include arrays of InGaAs, extended InGaAs, PbS, PbSe, Si, MCT, or the like. Light collection optics such as fiber optics, lenses, and mirrors are commonly used in various configurations within a spectrometer to direct light from the source to the detector by way of a sample. The mode of operation may be diffuse transmission, diffuse reflectance, or transflectance. Due to changes in performance of the overall spectrometer, reference wavelength standards are often scanned. Typically, a wavelength standard is collected immediately before or after the interrogation of the tissue or at the beginning of the day, but may occur at times far removed such as when the spectrometer was originally manufactured. A typical reference wavelength standard would be polystyrene or a rare earth oxide such as holmium, erbium, or dysprosium oxide. Many additional materials exist that have stable and sharp spectral features that may be used as a reference standard.
The interface of the glucose analyzer to the tissue includes a module where light such as near-infrared radiation is directed to and from the tissue either directly or through a light pipe, fiber-optics, a lens system, or a light directing mirror system. The area of the tissue surface to which near-infrared radiation is applied and the area of the tissue surface the returning near-infrared radiation is detected from are different and separated by a defined distance and selected to target a tissue volume conducive for the measurement of the property of interest. The patient interface module may include an elbow rest, a wrist rest, a hand support, and/or a guide to assist in interfacing the illumination mechanism of choice and the tissue of interest. Generally, an optical coupling fluid is placed on the sampling surface to increase incident photon penetration into the skin and to minimize specular reflectance from the surface of the skin. Important parameters in the interface include temperature and pressure.
The sample site is the specific tissue of the subject that is irradiated by the spectrometer system and the surface or point on the subject the measurement probe comes into contact with. The ideal qualities of the sample site include homogeneity, immutability, and accessibility to the target analyte. Several measurement sites may be used, including the abdomen, upper arm, thigh, hand (palm or back of the hand), ear lobe, finger, the volar aspect of the forearm, or the dorsal part of the forearm.
In addition, while the measurement can be made in either diffuse reflectance or diffuse transmittance mode, the preferred method is diffuse reflectance. The scanning of the tissue can be done continuously when pulsation effects do not affect the tissue area being tested, or the scanning can be done intermittently between pulses.
The collected signal (near-infrared radiation in this case) is converted to a voltage and sampled through an analog-to-digital converter for analysis on a microprocessor based system and the result displayed.
Preprocessing
Several approaches exist that employ diverse preprocessing methods to remove spectral variation related to the sample and instrumental variation including normalization, smoothing, derivatives, multiplicative signal correction (Geladi, P., D. McDougall and H. Martens. “Linearization and Scatter-Correction for Near-infrared Reflectance Spectra of Meat,” Applied Spectroscopy, vol. 39, pp. 491-500, 1985), standard normal variate transformation (R. J. Barnes, M. S. Dhanoa, and S. Lister, Applied Spectroscopy, 43, pp. 772-777, 1989), piecewise multiplicative scatter correction (T. Isaksson and B. R. Kowalski, Applied Spectroscopy, 47, pp. 702-709, 1993), extended multiplicative signal correction (H. Martens and E. Stark, J. Pharm Biomed Anal, 9, pp. 625-635, 1991), pathlength correction with chemical modeling and optimized scaling (“GlucoWatch Automatic Glucose Biographer and AutoSensors”, Cygnus Inc., Document #1992-00, Rev. March 2001), and FIR filtering (Sum, S. T., “Spectral Signal Correction for Multivariate Calibration,” Doctoral Dissertation, University of Delaware, Summer 1998; Sum, S. and S. D. Brown, “Standardization of Fiber-Optic Probes for Near-Infrared Multivariate Calibrations,” Applied Spectroscopy, Vol. 52, No. 6, pp. 869-877, 1998; and T. B. Blank, S. T. Sum, S. D. Brown and S. L. Monfre, “Transfer of near-infrared multivariate calibrations without standards,” Analytical Chemistry, 68, pp. 2987-2995, 1996). In addition, a diversity of signal, data or pre-processing techniques are commonly reported with the fundamental goal of enhancing accessibility of the net analyte signal (Massart, D. L., B. G. M. Vandeginste, S. N. Deming, Y. Michotte and L. Kaufman, Chemometrics: a textbook, New York: Elsevier Science Publishing Company, Inc., 215-252, 1990; Oppenheim, Alan V. and R. W. Schafer, Digital Signal Processing, Englewood Cliffs, N.J.: Prentice Hall, 1975, pp. 195-271; Otto, M., Chemometrics, Weinheim: Wiley-VCH, 51-78, 1999; Beebe, K. R., R. J. Pell and M. B. Seasholtz, Chemometrics A Practical Guide, New York: John Wiley & Sons, Inc., 26-55, 1998; M. A. Sharaf, D. L. Illman and B. R. Kowalski, Chemometrics, New York: John Wiley & Sons, Inc., 86-112, 1996; and Savitzky, A. and M. J. E. Golay. “Smoothing and Differentiation of Data by Simplified Least Squares Procedures,” Anal. Chem., vol. 36, no. 8, pp. 1627-1639, 1964). The goal of all of these techniques is to attenuate the noise and instrumental variation without affecting the signal of interest.
While methods for preprocessing effectively compensate for variation related to instrument and physical changes in the sample and enhance the net analyte signal in the presence of noise and interference, they are often inadequate for compensating for the sources of tissue related variation. For example, the highly nonlinear effects related sampling different tissue locations can't be effectively compensated for through a pathlength correction because the sample is multi-layered and heterogeneous. In addition, fundamental assumptions inherent in these methods, such as the constancy of multiplicative and additive effects across the spectral range and homoscadasticity of noise are violated in the non-invasive tissue application.
Near-IR Calibration
One noninvasive technology, near-infrared spectroscopy, has been heavily researched for its application for both frequent and painless noninvasive measurement of glucose. This approach involves the illumination of a spot on the body with near-infrared (NIR) electromagnetic radiation, light in the wavelength range of 700 to 2500 nm. The light is partially absorbed and scattered, according to its interaction with the constituents of the tissue. With near-infrared spectroscopy, a mathematical relationship between an in-vivo near-infrared measurement and the actual blood glucose value needs to be developed. This is achieved through the collection of in-vivo NIR measurements with corresponding blood glucose values that have been obtained directly through the use of measurement tools such as the YSI, HemoCue, or any appropriate and accurate traditional invasive or alternative invasive reference device.
For spectrophotometric based analyzers, there are several univariate and multivariate methods that can be used to develop this mathematical relationship. However, the basic equation which is being solved is known as the Beer-Lambert Law. This law states that the strength of an absorbance/reflectance measurement is proportional to the concentration of the analyte which is being measured as in equation 3,A=εbC   eq. 3where A is the absorbance/reflectance measurement at a given wavelength of light, ε is the molar absorptivity associated with the molecule of interest at the same given wavelength, b is the distance (or pathlength) that the light travels, and C is the concentration of the molecule of interest (glucose).
Chemometric calibration techniques extract the glucose related signal from the measured spectrum through various methods of signal processing and calibration including one or more mathematical models. The models are developed through the process of calibration on the basis of an exemplary set of spectral measurements known as the calibration set and an associated set of reference blood glucose values based upon an analysis of fingertip capillary blood, venous, or alternative site samples. Common multivariate approaches requiring a set of exemplary reference glucose concentrations and an associated sample spectrum include partial least squares (PLS) and principal component regression (PCR). Many additional forms of calibration are well known in the art such as neural networks.
Because every method has error, it is beneficial that the primary device, which is used to measure blood glucose be as accurate as possible to minimize the error that propagates through the mathematical relationship which is developed. While it appears intuitive that any U.S. FDA approved blood glucose monitor could be used, for accurate verification of the secondary method a monitor which has an accuracy of less than 5% is desirable. Meters with increased error such as 10% are acceptable, though the error of the device being calibrated may increase.
Currently, no device using near-infrared spectroscopy for the noninvasive measurement of glucose has been approved for use by persons with diabetes due to technology limitations that include poor sensitivity, sampling problems, time lag, calibration bias, long-term reproducibility, stability, and instrument noise. Fundamentally, however, accurate noninvasive estimation of blood glucose is presently limited by the available near-infrared technology, the trace concentration of glucose relative to other constituents, and the dynamic nature of the skin and living tissue of the patient. Further limitations to commercialization include a poor form factor (large size, heavy weight, and no or poor portability) and usability. For example, existing near-infrared technology is limited to larger devices that do not provide (nearly) continuous or automated measurement of glucose and are difficult for consumers to operate.
Clearly, a need exists for a completely noninvasive approach to the measurement of glucose that provides a nearly continuous readings in an automated fashion.